Dear Colleague Letters
Reported Rifapentine Impurity
June 18, 2020
Rifapentine (supplied as Priftin® 150 mg film-coated tablets manufactured by Sanofi) is part of a 3-month regimen with isoniazid (3HP) for treating latent tuberculosis infection (LTBI) and preventing TB disease. It has also been used in several recent and ongoing CDC-funded clinical trials. Priftin® is the only rifapentine product approved by the U.S. Food and Drug Administration (FDA). In June 2020 Sanofi alerted the Division of Tuberculosis Elimination, other health agencies, and stakeholders worldwide about a newly detected impurity in Priftin®. The impurity, 1-cyclopentyl-4-nitrosopiperazine, is a nitrosamine and a potential carcinogen. It was detected through testing based upon recently adopted regulatory standards to assay all medications for nitrosamines. (1,2) Low levels of the impurity have been detected in some rifapentine drug substance and in some market-ready Priftin® drug product batches at production facilities in Italy. The company is investigating the source of this impurity and any safety implications, and has communicated with FDA. A follow-up submission of the results of Sanofi’s investigation for discussion with FDA (including a benefit-risk evaluation) is anticipated in July. More background information about nitrosamine impurities in drug products is available on the FDA website. (3)
As a precautionary measure, Sanofi has paused the release of Priftin® from its production sites. This is expected to affect availability of the drug in the United States. This pause is in addition to the ongoing shortage that has affected the U.S. supplies of Priftin® since late 2019, and which was attributed to increased global demand. The investigation underway is the result of chemical testing of drug product and drug substance, and not a consequence of any observed safety signal in the pharmacovigilance databases. At this time, neither FDA nor Sanofi has requested a recall of the Priftin® supply that has already been distributed. FDA has not issued any new advisory about Priftin®. Neither FDA nor Sanofi has recommended that patients presently taking Priftin® as part of 3HP for treating LTBI discontinue this regimen. If a clinician or a patient prefers to discontinue 3HP, treatment for LTBI can be restarted with a complete alternative regimen, or it can be completed with a proportionate duration of an alternative regimen.
The 3HP treatment regimen should not be started for new patients until shipments of Priftin® resume and local supplies are reestablished. Other short-course regimens for treating LTBI — 4 months of daily rifampin or 3 months of daily isoniazid and rifampin — are recommended for their effectiveness and tolerability, per CDC’s updated guidelines on treating LTBI. (4) When directly observed therapy (DOT) is preferred, regimens of 6 or 9 months of isoniazid administered twice weekly can be considered because the intermittent dosing schedule is useful for DOT. However, these twice-weekly regimens have long durations and unconfirmed tolerability and efficacy.
Please share this notice with your partners in TB prevention such as clinicians at community health centers or correctional facilities. We will send updates about Priftin® when Sanofi and FDA share new information. Please coordinate your efforts with jurisdictional TB control authorities, https://www.cdc.gov/tb/links/default.htm. Send questions by e-mail to RPTqueries@cdc.gov. We will monitor this mailbox daily including weekends.
Terence Chorba, MD, DSc
Chief, Field Services Branch, Division of Tuberculosis Elimination
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
Centers for Disease Control and Prevention
1600 Clifton Road NE (US 12-4), Atlanta, GA 30329
- https://www.fda.gov/regulatory-information/search-fda-guidance-documents/m7r1-assessment-and-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potentialexternal icon
- https://database.ich.org/sites/default/files/Q3A%28R2%29%20Guideline.pdfpdf iconexternal icon and https://database.ich.org/sites/default/files/Q3B%28R2%29%20Guideline.pdfpdf iconexternal icon
- https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medicationsexternal icon